Single Cell Proteomics

Deep scRNA-seq missed it. Single-cell proteomics found it.
We profiled thousands of single PBMCs — proteomes and transcriptomes side by side — and uncovered functional coordination undetectable in the deepest scRNA-seq we could perform.

PBMCs are widely studied cells in single-cell biology. Millions of PBMCs have been analyzed by scRNA-seq. Have we seen it all ?

Interestingly, single-cell mass spectrometry (plexDIA) quantified more protein-coding gene products per cell than the RNA measurements, with substantially higher data completeness. The consistency and quantification accuracy makes it possible to ask a challenging question:

𝐇𝐨𝐰 𝐝𝐨 𝐠𝐞𝐧𝐞 𝐩𝐫𝐨𝐝𝐮𝐜𝐭𝐬 𝐯𝐚𝐫𝐲 𝐭𝐨𝐠𝐞𝐭𝐡𝐞𝐫 𝐟𝐫𝐨𝐦 𝐜𝐞𝐥𝐥 𝐭𝐨 𝐜𝐞𝐥𝐥 𝐰𝐢𝐭𝐡𝐢𝐧 𝐭𝐡𝐞 𝐬𝐚𝐦𝐞 𝐜𝐞𝐥𝐥 𝐭𝐲𝐩𝐞 ?

The protein measurements revealed cell-type-specific proteome architecture -- shaped in part by protein stability, and complex coordination -- that was undetectable in our mRNA data. Specifically, protein covariation within a cell type suggests cell-type-specific protein-protein interactions and functional rewiring of biological pathways independent of abundance differences.

Some examples:
1️⃣ Arp2/3 complex shows distinct protein-level coordination across immune cell types, while this organization is largely absent from the corresponding mRNA data.

2️⃣ Protein covariation reveal an axis of translational states in B cells that tracks inversely with the abundance cytokine GDF6, suggesting reciprocal regulation of protein synthesis and GDF6 priming.

The broader message is simple:

🔷 Single-cell proteomics opens a new window to a layer of functional coordination that had remained remained undetected.

We are excited to open this window wider and investigate deeper !
https://www.biorxiv.org/content/10.64898/2026.09.11.751068v1.full

Rapid technological advances are allowing researchers to identify thousands of proteins in individual cells, revealing the hidden mechanisms underlying development and disease.

Probing the proteome at cellular scale Rapid technological advances are allowing researchers to identify thousands of proteins in individual cells, revealing the hidden mechanisms underlying development and disease.

Thinking on the timescale of days & weeks, progress can feel frustratingly slow.

Shifting to the timescale of years, the progress is spectacular: Often faster than expected.

The arc of technology development has been awesome. The best is yet to come 🚀

Single-Cell Proteomic Technologies: Tools in the Quest for Principles Over the last decade, proteomics analysis of single cells by mass spectrometry transitioned from an uncertain possibility to a set of robust and rapidly advancing technologies supporting the accurate quantification of thousands of proteins. We review the major drivers of this progress, from establis...

Single-cell proteomics helped discover the earliest symmetry breaking during mammalian development.

https://www.cell.com/cell/fulltext/S0092-8674(25)01255-3